Stent restenosis is the most unfavorable complication of interventional treatment for coronary heart disease. We already know from various literature sources that the causes for stent restenosis in patients are both mechanical damage (partial opening, stent breakage, extended stented area, calcification, incomplete stent coverage of atherosclerotic plaque, weak radial stiffness of the stent metal frame, lack of stent drug coating), and the neointimal hyperplasia formation which is closely related to the de novo atherosclerosis development, being a predictor of the recurrent cardiovascular event.

Considering this event, it is necessary to understand all the pathogenetic and pathophysiological processes of atherosclerosis. This review aims to comprehensively highlight the main issues of pathogenesis and the development of stent restenosis in the coronary artery after percutaneous transluminal coronary angioplasty. The review is based on relevant publications found by a selective search of PubMed, Google Scholar, Scopus, Web of Science, and eLibrary, including works published within the last 20 years. The influence of various factors of the pathogenetic process on the risk of stent restenosis has been demonstrated.

stent restenosis, pathogenesis, inflammation, percutaneous transluminal angioplasty.

The introduction of percutaneous coronary intervention (PCI) has revolutionized the treatment of patients with obstructive coronary artery disease (CAD), including patients with acute myocardial infarction.^[1] In addition, the development of drug-eluting stents (DES) is successfully aimed at the problem of neointimal excess growth in the stented segment.^[2] However, this success was achieved at the cost of a significant delay in vascular healing due to the powerful effects of the released antiproliferative drugs.^[3] According to the 2018 ESC/EACTS Guidelines on Myocardial Revascularization, restenosis associated with CAD should be treated with repeat revascularization, and repeat PCI remains the strategy of choice for most of these patients.^[4] In-stent restenosis (ISR) is the healing process of the damaged vessel after stenting which is detected in approximately 10%–40% of patients.^[5] Long-term stent-related events have not been significantly reduced, despite recent advances in stent technology.^[6] High rates of ISR associated with bare-metal stents (BMSs) led to the development of DESs, which modified the healing process after stent implantation, attenuating neointimal formation, and resulting in a reduction of the incidence of ISR to rates ranging from 5% to 10%.^[7,8] With the invention of various generations of coated stents, their frequency has significantly decreased to 12%-15%, but the problem of restenosis is still not completely solved.^[9]

For the symptomatic treatment of atherosclerosis narrowing the lumen, percutaneous transluminal intervention was established, which has a high success rate, accompanied by low periprocedural complications. Despite proper technical success, the vascular events recurrence rate of up to 20% remains during the first 12 months.^[10,11] Although there is a decrease in the number of late thrombotic events when using new generation DES, late stent insufficiency remains a problem after stent installation. Neoatherosclerosis in the stent has become an important factor contributing to late vascular complications, including very late stent thrombosis and late restenosis in the stent.^[12] Histologically, neoatherosclerosis is characterized by accumulation of lipid foamy macrophages in the neointima with the formation of a necrotic nucleus and/or calcification, or without them. The development of neoatherosclerosis can occur months or years after the installation of a stent, whereas atherosclerosis in native coronary arteries develops for decades. Early development of neoatherosclerosis was identified not only in first-generation DES, but also in second-generation DES. The mechanisms underlying the rapid development of neoatherosclerosis remain unknown. Plaque rupture in the stent is probably the cause of most of the thrombotic events associated with neoatherosclerosis, while it can also be a substrate of restenosis in the stent, since thrombosis can occur either symptomatically or asymptomatically.

The purpose of this review is to highlight the main pathophysiological processes and to display possible markers of the diagnosis of CAD progression based on the analysis and review of domestic and international literature.

The work with the literature included the search for up-to-date original papers in PubMed, Google Scholar, Scopus, Web of Science, and JACC describing the contribution of immune processes to the pathogenesis of various phenotypes of restenosis in the stent. The search period was 20 years, but preference was given to current studies. The following key phrases were used to search the literature: inflammation, restenosis, atherosclerosis, immune system, tumor necrosis factor (TNF) and interleukin (IL)-1, IL-6, lipoprotein-associated phospholipase A2 (Lp-LA2), myeloperoxidase, pentraxin-3, proteases such as matrix metalloproteinase-9, and C-reactive protein (CRP) measured by high-sensitivity analysis (hs-CRP), lipoprotein (a) [Lp (a)], apolipoprotein A-II, growth differentiation factor (GDF) in in-ISR, and proliferation and migration of vascular smooth muscle cells (VSMCs) in the development of neoatherosclerosis. The full-text sources were then analyzed to determine which publications were relevant to the review’s aim and to assess their significance. The exclusion criteria were duplicate publications, review articles without a detailed description of scientific results, and authors’ opinions. A total of 25849 papers were initially found in these databases according to the key words. After using the exclusion criteria, the review included 46 of the most relevant and significant papers (Fig. 1).

Figure 1.

Selection of papers for the review according to the PRISMA methodology.

There are several factors that may contribute to the development of stent restenosis. These include biological factors, such as stent drug-eluting resistance and hypersensitivity; mechanical factors: incomplete opening of the device, its breakage or rupture, uneven distribution of the drug in the stent, polymer peeling, and there are also technical reasons, namely, barotrauma of the outstented segment, and residual uncovered atherosclerotic plaques. Interestingly, the predictors that contribute to the formation of restenosis in a drug-eluting stent do not differ from those in the implantation of a metal one. Factors such as a history of diabetes mellitus (DM), complex injury, small vessel diameter, and a long or non-expanded stent are equally common in both groups.^[13]

According to the literature, the metabolic syndrome is characterized by insulin resistance, endothelial dysfunction, in addition to low-intensity inflammation and oxidative stress, which are common risk factors (RF) for the development of atherosclerosis.^[14]

Thus, according to Cheng et al.^[15], RFs affecting restenosis after PCI in patients with CAD, a clinical study based on 1-year follow-up showed that 93 cases among 1132 cases had ISR with a total frequency of 8.21%.

One-dimensional and multidimensional logistic regression analyses showed that postoperative levels of hypersensitive hs-CRP (OR=2.309, 1.579–3.375 mg/L), postoperative levels of homocysteine (HCY) (OR=2.202, 1.268–3.826 mmol/L), history of DM (OR=1.955, 1.272–3.003), coronary bifurcation lesions (OR=3.785, 2.246–6.377), and stent length (OR=1.269, 1.179–1.365 mm) were independent risk factors for ISR after PCI.^[15]

An increasing number of scholarly publications prove the significant contribution of the immune system to the development and progression of ISR, and the inflammatory theory has repeatedly been confirmed in experimental studies. Atherosclerosis is an important cause of morbidity and mortality in the world^[16], and the studies of diagnostic markers are important for early diagnosis and quality treatment of CAD progression. Over the past decades, the efforts of scientists around the world have been focused on studying the role of various components of cellular and humoral immunity in atherogenesis. It is believed that dendritic cells (DC) located in the arterial wall are able to capture particles of oxidized low-density lipoproteins (Ox-LDL) and present them on their surface as an antigen for native T-cells. One of the key functions of DC is the production of the chemokine CCL17, under the influence of which CCR4 receptors located on the surface of T lymphocytes move to the location of DC.^[17] According to the research of Karpov et al., a moderately positive correlation has been found between the number of T-helpers carrying the CCR4 receptor and the Gensini score, as well as a moderately negative correlation between the level of CCL17 chemokine in peripheral blood and the relative number of T-helpers expressing the CCR4 receptor.

The data obtained suggest that the chemokine CCL17 and the CCR4 receptor play a role in initiating the T-cell immune response in atherosclerosis.^[17] It is worth noting that the effect of statins on the composition of immunocompetent cells could not be determined in this study because all of the patients were initially on cholesterol-lowering therapy. In the literature, the data on the effect of statins on the content of immunocompetent cells in the blood, in particular on the level of CD3+CD4+, are quite common.‌^[18] A more in-depth investigation of the issue, as well as determination of the degree of CCR4 expression by T-lymphocytes of various subtypes, simultaneous determination of the level of DC in the blood, exclusion of the influence of RF for CAD and the treatment received, will allow us to better understand the mechanisms of immuno-inflammatory reactions in atherosclerosis and develop new methods of immunotropic therapy for the disease.

Studies by Kazemian et al. have shown that there is a link between high levels of LDL and Lp(a) in the bloodstream and the likelihood of restenosis in the stent; moreover, the studies show that Lp(a) can stimulate the proliferation of VSMCS.^[19]

In many studies, type 2 DM repeatedly appears as one of the significant RFs for the development of cardiovascular events by 1.7 times with a single-vascular lesion, in the presence of multifocal atherosclerosis – already by 2.8 times.^[20] And also in patients after myocardial revascularization in the presence of type 2 DM is already associated with an unfavorable cardiovascular prognosis. Patients with DM are characterized by high platelet reactivity in relation to thrombosis. The results of recent studies have shown that patients with DM have increased platelet volume, increased their sensitivity to the main inducers of thrombosis.^[21] This factor was also noted in the study by Biazrova SV^[22] which demonstrated that patients who undergo coronary stenting with drug-coated stents and have a higher blood level of platelets carrying the leukocyte antigen CD45+ (CD45+ platelets) on their surface have a higher incidence of restenosis compared to patients with lower level of CD45+ platelets. An increase in the level of CD45+ platelets in the blood of patients after coronary artery stenting using drug-coated stents has a closer relationship with the occurrence of restenosis in patients with diabetes mellitus compared with patients without this disease.^[22]

Zhu et al. identified 10 genes (STAT3, IL1RN, C5AR1, CXCL16, IL17RA, SLC11A1, TLR2, IL1B, LYN, and CKAP4) that may be new diagnostic signatures for atherosclerosis.^[23] However, there were some limitations in this study: firstly, due to the lack of information about cardiac RF of patients, such as age and gender, cardiac RF were not included in the WGCNA and logistic regression analysis. The selected genes may also be associated with cardiac RFs and not correlate directly with atherosclerosis. Secondly, although 10 potentially key genes have been identified, the specific biological functions and characteristics of these genes need to be further studied in the future. Thirdly, it is necessary to collect more clinical patients for further validation of this model.

Detection at the outpatient stage continues to be extremely low, even in the presence of clinical signs of the disease, not to mention asymptomatic forms.^[24] A number of studies have recently been published in which it has been repeatedly stated that the type, composition, morphology, and immunohistochemical characteristics of an unstable (vulnerable, prone to rupture) atherosclerotic plaque are more important than the size of the atheroma or the degree of arterial stenosis.^[25] The search for effective therapeutic targets and early diagnosis of restenosis inside the stent leads to a high interest in the pathogenesis of this condition. The main pathogenetic mechanisms of the development of RVS are elastic collapse of the vessel lumen, parietal thrombosis and hyperplasia of the neointima, leading to pathological remodeling of the vascular wall. Mechanical damage to the intima media of the arteries and hypersensitivity to stent materials are considered as the starting moment.‌^[26] It was previously known that injury to the vascular wall during the intervention leads to the development of a local inflammatory reaction, adhesion, activation and aggregation of platelets with the formation of a parietal thrombus, migration and proliferation of smooth muscle cells (MMC) and reendothelization, as well as to the synthesis of extracellular matrix components (hyaluronic acid, fibronectin, osteopontin and vibronectin). All these processes are physiological and necessary to restore the anatomical and functional integrity of the vascular wall. However, in some cases, they acquire a pathological character and lead to the appearance of neointima hyperplasia and chronic vasoconstriction. According to a number of authors, stenting prevents elastic recoil, but does not prevent the development of thrombosis, inflammation, and hyperplasia of the neointima.

The structure of the covering of an atherosclerotic plaque includes many components of the extracellular matrix (collagen, elastin, proteoglycans and glycosaminoglycans), factors affecting the formation and destruction of these components are of great importance in stabilizing the plaque. At the same time, the listed macromolecules of the extracellular matrix can capture lipoproteins and contribute to the accumulation of lipids in the intima. It is known that atherosclerotic plaques rich in lipids, and not a connective tissue elements and uncalcined become more ‘soft’ and dangerous in terms of damage and thrombosis development. Cytokines are able to stimulate the secretion of matrix metalloproteinases (MMPs) by atheroma cells (mainly macrophages, but also endothelial, smooth muscle, foam cells). MMPs (collagenases, gelatinases, stromelysins, etc.) obtain a degrading ability towards almost all components of the extracellular matrix. Pronounced stimulating effect on the transcription and synthesis of MMPs was found in neurohumoral agents traditionally associated with remodeling processes: angiotensin II, endothelin, catecholamines. The secretion of MMPs can be influenced not only by cytokines, but also by growth factors, some chemical agents, etc. The activity of MMP in the plaque is parallel to an increase in inflammatory cell infiltration in it and an increase in the level of cell apoptosis.^[27,28]

It was already noted earlier that neointimal hyperplasia is one of the main factors contributing to restenosis after angioplasty procedures. The development of restenosis is based on the complex interaction of various mechanical and biological factors caused by the revascularization procedure of the affected vascular network and concomitant vascular trauma. The mechanism by which postangioplastic restenosis develops seems to depend on whether the intervention was performed with a stent or balloon angioplasty. In the case of a procedure without a stent, early arterial recoil and negative vascular remodeling are important factors. On the contrary, restenosis after stent implantation (restenosis in the stent) primarily contributes to neointimal formation and neoatherosclerosis.^[29,30]

In their work, Ebert et al.^[31] described in sufficient detail the generation of neointimal hyperplasia on the example of various small animals, creating a vascular injury, as a consequence of which, an inflammatory reaction occurs with an increased set of immune cells, especially monocytes and macrophages, which quickly accumulate and differentiate into foam macrophages. Oxidative stress and increased release of cytokines and chemokines lead to proliferation and migration of VSMCs from the medium to the intima.

A detailed study of the cardiovascular system immune homeostasis is necessary to search for early predictors of noninvasive diagnosis of ISR and it is possible in the future to create and justify specific targets for immunotropic therapy. Currently, a number of clinical studies and meta-analyses are devoted to the investigation of new surface-decomposable DES with the functions of anticoagulation, antiproliferation and endothelialization.^[32] DES are widely used in the clinic because of their impressive ability to reduce restenosis. However, conventional biodegradable drug-coated polymers undergo volumetric erosion, which can induce internal catalysis that leads to high local acidity during the degradation process and causes adverse side effects.^[33]

In addition, human autopsy analysis showed that drug-eluting stents show greater deposition of proteoglycans compared to restenotic BMS, which may be a potential enhancer of neoatherosclerosis in DES, since extracellular matrix components such as proteoglycan are known to be associated with lipoprotein retention.^[34] Persistent apoptosis of macrophages and smooth muscle cells in stented lesions additionally contributes to the development of the necrotic nucleus.^[35] Pathological thickening of intima with a lipid pool is a sign of native atherosclerosis and plaque progression, whereas in neoatherosclerosis, the formation of a necrotic nucleus is mainly due to apoptosis of macrophages in the absence of a lipid pool, which ultimately leads to plaque rupture in the stent. It has already been noted that atherosclerosis in native coronary arteries develops for decades, while neoatherosclerosis in the stent appears to occur months or years after the stent is installed and quickly and more often in DES compared to BMS.^[31]

The mechanisms responsible for accelerated atherosclerosis in stented segments, especially in DES, remain little known; however, it is assumed that incompetent and dysfunctional endothelial coating of the stented segment contributes to this process.

The formation of neointima shows several parallels with the formation of de novo atherosclerosis. Talking about this process, it is necessary to understand all the pathophysiological stages.

The attention of health workers should be directed not only to the timeliness and completeness of medical high-tech care provision, but also to the improvement of preventive measures in atherosclerosis progression. Since the pathogenesis of restenosis inside the stent is multifactorial, differentiated risk stratification is necessary. The identification of predictors associated with the patient, stent and the lesion is especially important, since the most effective way to combat restenosis inside the stent is to prevent it. The patients with a higher risk of neointima formation in the stent should receive routine follow-up at the dispensary and intensive medication after percutaneous coronary intervention to control risk factors and reduce restenosis in the stent.

This review can be used to create a risk prediction model and develop an intervention strategy in the formation of in-stent restenosis in patients after very high-risk percutaneous coronary intervention.

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The authors have no funding to report.

The authors declares that there is no conflict of interest.